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Inhibition of coronary restenosis by antithrombin III in atherosclerotic swine
M N Ali1, W Mazur, N S Kleiman
1Department of Medicine, Baylor College of Medicine, Houston, Texas, USA.
Background:
Thrombin-mediated vascular smooth muscle cell proliferation has been implicated in coronary restenosis. Attempts to inhibit this mitogenic activity have recently focused on non-physiologic direct thrombin inhibitors, whereas endogenous thrombin inhibitors such as antithrombin III (ATIII) have received little attention. ATIII is the main physiologic inhibitor of thrombin and may thus be a potential therapeutic agent for prevention of restenosis.
Methods:
Human ATIII (125 U/kg) and heparin (200 U/kg) were administered to 12 atherosclerotic swine 30 min prior to inducing restenosis by oversized stent (left anterior descending and right coronary arteries; stent-to-artery ratio approximately 1.2) and balloon injury (circumflex; balloon artery ratio approximately 1.2). Eleven control swine received only heparin every 6 h for 24 h and were subjected to similar stent and balloon injury. Quantitative coronary angiography [change in minimal lumen diameter (delta MLD)] and morphometric analysis [percentage area stenosis (PAS)] were performed 4 weeks later.
Results:
ATIII activity (mean +/- SD) of treated swine increased from a baseline of 103 +/- 10% to a peak of 266 +/- 48%, whereas trough levels were maintained at 259 +/- 55% for 72 h by drug infusions every 6 h. The delta MLD, the primary angiographic endpoint in the balloon injured vessel was -0.57 +/- 0.33 mm in heparin group versus -0.26 +/- 0.27 mm in the ATIII group (P < or = 0.03). For stented vessels the delta MLD was -0.61 +/- 0.33 mm in the heparin group versus -0.41 +/- 0.37 mm in the ATIII group (P < or = 0.06). The PAS for the balloon injured vessels was 30 +/- 12% in the heparin group versus 19 +/- 14 in the ATIII group (P < or = 0.06). In stented vessels the PAS was 45 +/- 16% in the heparin group versus 38 +/- 16% in the ATIII group (P < or = 0.1).
Conclusion:
Supraphysiologic ATIII levels in combination with heparin inhibits the reduction in MLD in coronary arteries subjected to oversized balloon injury and demonstrates a beneficial trend in arteries subjected to oversized stent injury. These data provide cautious optimism for further investigation with ATIII to prevent coronary restenosis.
Insights
Antithrombin III (ATIII) combined with heparin showed potential in preventing coronary restenosis after balloon injury and stenting in swine. This study suggests ATIII may be a therapeutic agent for inhibiting vascular smooth muscle cell proliferation.
Area of Science:
- Cardiovascular Research
- Thrombosis and Hemostasis
- Vascular Biology
Background:
- Thrombin promotes vascular smooth muscle cell proliferation, contributing to coronary restenosis.
- Endogenous thrombin inhibitors like antithrombin III (ATIII) are understudied for restenosis prevention.
- ATIII is the primary physiological inhibitor of thrombin.
Purpose of the Study:
- To investigate the efficacy of ATIII in preventing coronary restenosis in a swine model.
- To evaluate ATIII's role in inhibiting thrombin-mediated vascular smooth muscle cell proliferation.
Main Methods:
- A swine model of coronary restenosis was created using oversized stents and balloon angioplasty.
- Swine received human ATIII (125 U/kg) or heparin (200 U/kg) plus ATIII, with controls receiving only heparin.
- Quantitative coronary angiography and morphometric analysis were performed after 4 weeks.
Main Results:
- ATIII administration significantly reduced the reduction in minimal lumen diameter (MLD) after balloon injury (P < 0.03).
- A beneficial trend was observed in reducing MLD reduction in stented vessels (P < 0.06).
- Percentage area stenosis (PAS) was reduced in balloon-injured vessels (P < 0.06) and showed a trend in stented vessels (P < 0.1).
Conclusions:
- Supraphysiological ATIII levels, with heparin, inhibit MLD reduction in balloon-injured coronary arteries.
- ATIII demonstrates a beneficial trend in preventing restenosis in stented arteries.
- Further investigation of ATIII for coronary restenosis prevention is warranted.